The molecular mechanisms that lead to increased restenosis in T2DM are unknown. Vascular smooth muscle cell (VSMC) proliferation plays a key role in restenosis following vascular injury, and glucose, insulin, and oxidative stress increase VSMC growth. Moreover, in animal models of T2DM, there is increased VSMC proliferation in response to injury. Leukocyte type 12/15 lipoxygenase (12LO) has been implicated as a key mediator of enhanced VSMC proliferation and neointimal formation in response to injury in animal models of T2DM. Our preliminary data clearly demonstrates that 12LO regulates VSMC growth, one potential mechanism for the accelerated response to injury in diabetes. We further demonstrate that 12LO-induced proliferation of VSMC is mediated by the helix-loop-helix transcription factor Id3 (a key regulator of insulin and glucose mediated gene transcription). We have demonstrated in multiple models of insulin resistance and type 2 DM, that Id3 expression is significantly increased. Mechanistic studies demonstrate that Id3 promotes G1-S transition leading to increased VSMC growth and that phosphorylation of Id3 on serine 5 regulates this event. In this renewal application, we propose to extend our in vitro mechanistic findings and previous in vivo expression studies to demonstrate that the 12LO/ld3 pathway is a key mediator of the vascular response to injury in vivo in animals models of type 2 DM. Furthermore, we propose to identify the cis and trans-acting elements that mediate 12LO-induced increases in Id3 expression and VSMC growth and confirm their role in vivo in the response to injury in T2DM . Hypotheses: Type 2 DM modulates the response to vascular injury via regulation of Id3 expression and activity and VSMC growth. This effect is mediated by 12LO-induced nuclear factor expression leading to enhanced Id3 expression and/or serine 5 phosphorylation of Id3. To extend our exciting findings from VSMC culture studies in vivo in an animals model of vascular response to injury in T2DM and to address this central hypothesis, we propose the following aims. Aim 1: Establish the essential role of Id3 in the accelerated neointimal formation in response to injury in diet-induced mouse models of type 2 DM. Aim 2: Evaluate in vivo the 12LO/ld3 pathway leading to accelerated VSMC growth and lesion formation. Aim 3c. Extend in vitro findings in vivo to confirm that the 12LO-response elements in the Id3 promoter required for Id3 transcription in culture also regulate Id3 transcription in vivo in response to injury in T2DM.